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Preventive Medicine and Public Health

Doweon Park

The class of Dr. Soneil Guptha on Thursday 8:30 PM

Preventing Strokes in the patients of Transient Ischemic Attack (TIA) caused by High

Blood Pressure or Diabetes Mellitus Type 2 with Acupuncture Treatments:

the cross sectional study by Doweon Park

DACM Fall 2017 San Diego, PCOM

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Abstract

Though stroke is the second leading cause of death in the world, whether acupuncture is

effective in preventing stroke for patients with TIA caused by comorbidity of high blood

pressure (HBP) or diabetes mellitus type 2 is unknown. This study investigates the effectiveness

of acupuncture in decreasing stroke risk among patients with TIA caused by high blood pressure

or diabetes mellitus type 2 using the cross sectional study. Three hundred subjects will be

initially enrolled into the study and will be randomized into one of three groups, consisting of

two cases for acupuncture and one control (each group consists of 100 subjects). Control group

will be treated using conventional western treatments and two cases of acupuncture treatments

with scalp acupuncture and body acupuncture together will be given on a basis of once a week

for initial 3 months protocol (12 treatments total), and reevaluated at 3rd month, 6th month, and

12th month time point. This will be the first study that compares the effects of acupuncture

treatments with the comorbidities of high blood pressure or diabetes mellitus type 2 regarding

possible reduced risks of strokes in the long term.

Keywords : acupuncture, high blood pressure, diabetes mellitus type 2, transient ischemic attack

(TIA), preventing stroke

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1. Background

1.1 Description of the condition

Stroke is the second leading cause of death in the world1. In the USA, stroke accounted for

about one of every 19 deaths in 2010. On average, someone dies of stroke every four minutes2.

Although age-standardized rates of stroke mortality have decreased worldwide in the past two

decades, the absolute numbers of people with first stroke (16.9 million), stroke survivors (33

million), stroke-related deaths (5.9 million), and disability-adjusted life-years (DALYs) lost (102

million) in 2010 were still high and had significantly increased since 1990 (68%, 84%, 26%, and

12% increase, respectively), imposing a great burden on families and communities in low-

income and middle-income countries3 .

1.2 The definition of transient ischemic attack (TIA)

The definition of transient ischemic attack (TIA) has evolved over the past few decades. A TIA

is generally considered as one of warning signs of a stroke. Classically, a TIA was defined as a

sudden, focal neurological deficit of less than 24 hours in duration. This definition has evolved to

incorporate ongoing advances in neuroimaging and acute stroke protocols. For instance, 30%–

50% of patients diagnosed to have TIA using the classical ‘time-based’ criteria were found to

have central nervous system (CNS) infarction on diffusion-weighted magnetic resonance

imaging (MRI).4 More recently, the 2009 American Heart Association/American Stroke

Association’s ‘tissue-based’ definition of TIA stated that it is “a transient episode of

neurological dysfunction caused by focal brain, spinal cord or retinal ischemia without acute

infarction”.4

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1.3 The diagnosis of Transient Ischemic Attack

The diagnosis of CNS infarction is based both on careful clinical assessment and evidence on

advanced neuroimaging5. Early neuroimaging is crucial, as it affects decision-making on time-

sensitive interventions in acute stroke management. On MRI, a lack of evidence of infarction in

patients with symptoms of cerebral ischemia distinguishes a TIA from an acute ischemic stroke.

In cases where advanced neuroimaging is not available, CNS infarction is diagnosed when focal

neurological deficits persist for 24 hours or more, or until death, whichever is earlier. Proper

documentation of evidence for diagnosing TIA or acute stroke is important in view of

medicolegal ramifications in insurance claims. TIA and acute ischemic stroke are part of the

cerebral ischemia spectrum. TIA represents a milder event in which neurological cell death or

infarction has not yet occurred, and thus may be prevented6.

1.4 Risk factors for TIA

Both TIAs and acute ischemic strokes occur because of cerebral ischemia and are associated

with vascular risk factors13. Table I summarizes the established modifiable risk factors of TIA

and acute ischemic stroke14.

Table I. established modifiable risk factors of transient ischemic attack and stroke.

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And the 2010 INTERSTROKE study found that five modifiable risk factors (hypertension,

current smoking, abdominal obesity, unhealthy diet and physical inactivity) accounted for more

than 80% of strokes15.

1.5 Description of the intervention

Acupuncture is one of the main modalities of treatment in traditional Chinese medicine and

can be traced back more than 3000 years in China7. Possible mechanisms of the effects of

acupuncture on neurological conditions include stimulation of neuronal cell proliferation8,

facilitation of neural plasticity9, reduction of the post-ischemic inflammatory reaction10, and

prevention of neuronal apoptosis11. One report found that acupuncture intervention based on

promoting the circulation of the Governor Vessel and regulating mentality achieves the superior

efficacy on TIA and less adverse reactions as compared with aspirin12.

However, whether acupuncture is effective in preventing stroke for patients with TIA caused by

comorbidity of high blood pressure (HBP) or diabetes mellitus type 2 is unknown. This study

investigates the effectiveness of acupuncture in decreasing stroke risk among patients with TIA

caused by high blood pressure or diabetes mellitus type 2 using the cross sectional study.

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2. Methods

2.1 Standard of care treatment

Standard of care treatment include high-intensity physical activity, blood pressure control,

statin therapy, and antiplatelet agents. Significant relative risk reduction of stroke may be

achieved with high-intensity physical activity (64%)16, blood pressure control (30%–40%)17,18,

statin therapy (16%–33%)19,20, and antiplatelet agents (18%–37%)21,22.

2.2 Study design

This study is a cross sectional study consisting of three cohorts. The control cohort group will

receive only standard of care treatment based on each participant’s medical conditions related to

TIA and the other two treatment cohort groups with the comorbidity of high blood pressure or

type 2 diabetes mellitus will receive standard of care treatment based on each participant’s

medical conditions and acupuncture. Diabetes will be defined by a fasting blood glucose of ≥

126 mg/dL on ≥ 2 occasions or treatment with hypoglycemic medications, and hypertension by

blood pressure ≥140/90 mmHg on ≥2 occasions or if patient was being treated with anti-

hypertensive drugs23.

Volunteers will be informed about the investigation verbally and using written information.

Subjects will have time to decide whether to take part in the study, and discuss any questions

they have about the investigation. Each participant will give informed written consent to be

enrolled in the investigation. Three hundred subjects will be initially enrolled into the study and

will be randomized into one of three groups, consisting of two cases for acupuncture and one

control (each group consists of 100 subjects). Each patient will have a number between 1 and 3,

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and each number will be assigned to one of our study groups. Neither participants nor the

researchers know which group will receive acupuncture intervention and which group will

undergo standard intervention. Only the acupuncturist will be informed of group allocations to

use the appropriate intervention for each participant.

Acupuncture treatment will be given on a basis of once a week for initial 3 months protocol

(12 treatments total), and reevaluated at 3rd month, 6th month, and 12th month. Scalp needles and

body acupuncture needles will be used as a main acupuncture treatment protocol (specific

acupuncture treatment details outlined in ‘Manipulations’ section). Patients in the control group

will only receive conventional care, which will be the same as the acupuncture group. However,

no acupuncture treatments will be given during the whole study period to the control group.

3. Subjects

3.1 Samples

300 patients between 35–80 years of age with TIA within the past 1 year will be included. The

treatment group of 200 patients with onset of stroke between two to twelve months will be

included with conventional treatment and acupuncture treatment. The control group of 100

patients with onset of stroke between two to twelve months will be included with only

conventional treatment.

3.2 Inclusion criteria

Patients between 35–80 years of age with TIA within past 1 year will be included. Patients

with onset of TIA between two to seven days beforehand, the NIHSS(National Institutes of

Health Stroke Scale) score between 5 and 14, and displaying clear consciousness and stable vital

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signs will be only included if it is their first incidence of stroke. We will exclude severe stroke

(the NIHSS score between 15 and 24) after the trial commencement, because the severe stroke

patients need more frequently skilled care, which may be beyond our treatment program.

3.3 Exclusion criteria

Excluded from the study will be patients who suffered from serious heart, liver, and kidney-

related diseases, or blood coagulation dysfunction, and patients unable to complete the MMSE

(Mini–Mental State Examination) test or bedside swallowing assessment (BSA). Congenital

disabilities will be also excluded. Patients who suffered POCI (Posterior Circulation Infarcts) in

OCSP (Oxford shire Community Stroke Project) classification, or received thrombolytic therapy

or who participated in other clinical trials within previous three months, and women who were

pregnant or breast-feeding will be also excluded from this study.

3.4 Intervention

Traditional Chinese style acupuncture will be used in accordance with the Advanced

Textbook of traditional Chinese Medicine and Pharmacology, and the textbook of Acupuncture

and Moxibustion Administration Methods24.

The acupuncture will be performed by three acupuncture doctors who have a master and

doctoral degree with more than five years of clinical experiences, and will have been trained

previously to perform the same protocols. For scalp acupuncture, two to three needles will be

penetrated through the top midline, the motor region (MS-6), and the sensory region (MS-7) of

the lesion side25.

Fig 1 Zone Chart

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In each session, the points for the

affected side of the body in the time of TIA related episode, acupuncture will be as follows: LI15

(Jianyu), LI11 (Quchi), LI10 (Shousanli), TE5 (Waiguan), and LI4 (Hegu) for upper extremities;

ST34 (Liangqiu), ST36 (Zusanli), GB34 (Yanglingquan), SP6 (Sanyinjiao), ST40 (Fenglong),

ST41 (Jiexi), and LR3 (Taichong) for lower limbs. The points for the experience of dysphagia

will be added as follow : GB20 (Fengchi), EX-HN14 (Yiming), BL10 (Tianzhu), GV16

(Fengfu), Gongxue (1 cun below GB20), and CV23 (Lianquan).For the experience of cognitive

impairment, GV20 (Baihui), GV24 (Shenting), GB13 (Benshen), EX-HN-1 (Sishencong) will be

added. Chinese-made Huan-Qui needles will be inserted 1-1.5 cun deep into the tissue, seeking a

pain response.

3.5 Manipulations

Manipulations of scalp acupuncture: the needles will be swiftly inserted into the subcutaneous

tissue of the scalp in a horizontal direction. When acupuncture needles (the stainless steel needle,

0.25 mm × 40 mm in size) reach the subgaleal layer and the practitioner feels the weak insertion

resistance, needles will be further inserted to the depth of 30 mm ~ 40 mm by twirling method.

Patients will be placed in a sitting position during the needle insertion, but they will be lying

down on the bed after insertion.

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Manipulations of body acupuncture: the needle will be inserted into the points to a depth of

between 30 mm and 40 mm according to different regions in a supine position. Manual

stimulation will be applied to the body acupoints until the patients experience the needling

sensation (called Deqi in Chinese acupuncture)12. For nape-acupuncture on dysphagia: after the

scalp acupuncture needle insertion, patients with dysphagia receive nape-acupuncture in a sitting

position during the needle insertion, then lie supine with a pillow padded under the occiput to

avoid the needles touching the bed. The retention of body acupuncture and nape-acupuncture

will be thirty minutes. The order of acupuncture treatment was as follows: For insertion: scalp

acupuncture-nape-acupuncture (for dysphagia)-body acupuncture. For withdrawing needles: the

body acupuncture-nape-acupuncture-the scalp acupuncture. Needles will be removed quickly,

within 1–2 min, and social interaction during the acupuncture session will be minimal.

4. Statistical Analysis

4.1 Data and Statistics

NIHSS, mainly developed for using in acute stroke trials, strongly predicts the likelihood of a

patient’s recovery after stroke at early stage 26. This measure will be used as a primary outcome

in this trial, and a good result of NIHSS may implicate a good functional recovery in a long-term

process. The SPSS software (Statistical Package for Social Sciences, IBM, Chicago, Illinois,

USA) will be used for statistical analysis with descriptive statistics (mean, median, interquartile

range, and standard deviation) being determined for each variable. In all cases, P ≤ 0.05 is

considered to be significant. The sample size will be calculated based on a former study

conducted in this field. The required sample size was estimated to be 100 patients in each study

group at a power of 80% and a confidence interval of 95%. Approximately 100 patients will be

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initially recruited to each group to allow for drop out and possibly do analysis in subgroups

(male, female). As acupuncture is still not very popular and common in USA, we believe that a

larger safety margin will be needed to allow for possible drop outs in the course of this rather

long-term study27.

4.2 Outcome measures

Participants will receive assessments at week 0 (baseline), week 12(after treatment) ,week

24(1st follow-up), and week 52 (2nd follow-up). The NIHSS index for neurologic deficit

evaluation will be used as the primary outcome measurements. Secondary outcome measures

include prospectively using functional outcome scales and HRQOL (Health-related Quality of

Life) scores. The functional outcome scales include the mRS (modified Rankin Scale) and the BI

(Barthel Index). The mRS is a disability scale ranging from no symptoms (0) to dead (6), and BI

is an ordinal measure of activities of daily living performance with scores ranging from complete

bedridden dependence (0) to full independence (100)28. We will use previously published

definitions of favorable outcome (BI of 95 or 100 and mRS score 0 or 1) at the 3-month, 6-

month, and 12-month time point29.

5. Significance

Acupuncture can exert its effect on blood pressure by several different mechanisms. In human

study, acupuncture has been shown to regulate blood pressure by changes in aldosterone, renin,

angiotensin II and endothelin- 1, and by regulating neurotransmitters including GABA,

serotonin, and endocannabinoids. The long lasting effects of the acupuncture can be attributed to

GABA and opioids in rVLM, neural circuitry between the ventrolateral and arcuate

periaqueductal grey matter, and by prolonging the increase in preproenkephalin mRNA levels

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and encephalin levels in the rVLM and arcuate. The role of renin, norepinephrine and

aldosterone have been shown to have a role in long-lasting inhibitory effects of acupuncture on

sympathetic activity in hypertensive patients who have undergone electroacupuncture

treatment31,31.

Also numerous experimental studies have demonstrated that acupuncture can correct various

metabolic disorders such as hyperglycemia, overweight, hyperphagia, hyperlipidemia,

inflammation, altered activity of the sympathetic nervous system and insulin signal defect, all of

which contribute to the development of insulin resistance. In addition, acupuncture has the

potential to improve insulin sensitivity. The evidence has revealed the mechanisms responsible

for the beneficial effects of acupuncture, though further investigations are warranted32.

To the best of our knowledge this will be the first study that compares the effects of

acupuncture treatments with the comorbidities of high blood pressure or diabetes mellitus type 2

regarding possible reduced risks of strokes in the long term.

Some caveats of this study merit comments. First, this study does not include differentiating

pattern diagnosis based on TCM principles which is commonly employed for the effective

treatment. Second, we might have to ignore comorbidities and underlying diseases, because

many risk factors can possible coexist and could have been complicated by other medical

diseases. Third, there is no differentiating in sampling in terms of demographic factors such as

age, sex, ethnicity, etc. And fourth, there is a possible blinding bias to patients and study

facilitators.

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